Propofol (2,6-Diisopropylphenol) is a well-known and widely used intravenous anesthetic agent. A significant advantage of using propofol is a rapid onset following infusion or bolus injection and the benefit of a very short recovery time, which requires minutes rather than hours. Propofol's hypnotic properties permit it to be used as both a sedative and to induce and maintain general anesthesia.
Chemically, propofol is a phenolic compound belonging to the same family. According to the Handbook of Pharmaceutical Excipient (Kibbe), phenols are mainly used as antimicrobial preservatives in parenteral pharmaceutical products. As a result of this, since propofol is the active agent and a phenolic compound, it could, under the optimal conditions, act as its own microbial retardation agent.
Propofol has limited water solubility, however it is easy to dissolve in soybean oil. As such, it must be incorporated with a solubilizing agent, surfactants or solvents to generate oil-in-water emulsions. The oil component of the emulsion is contained within a shell of the surfactants (egg lecithin), thus forming a “sunflower” structure, which can be seen in Table 1. Currently marketed propofol products are available as oil-in-water emulsions. The partition coefficient of propofol between soybean oil and water is 4,220 per our study for propofol.
DIPRIVAN® 1% consisting of 1% propofol, 10% soybean oil, 1.2% egg lecithin, and 2.25% glycerin, was originally released in 1989. However, within one year there were reports of an uncommonly high number of infections. Further investigation showed that despite the product labeling, various non-aseptic practices were being used (e.g., storing opened DIPRIVAN® for administration to multiple patients). As a result, the manufacturer altered the prescribing information to reinforce the need for aseptic handling, which includes immediate use after opening and one vial for each patient. While this change in the prescribing information and accompanying educational campaign did reduce the number of infections due to misuse, the problem was not completely solved. Despite the aforementioned efforts, in June 1993 another outbreak of infection was reported which included two deaths. The continued problems and high levels of infection caused the Food and Drug Administration (FDA) and Center for Disease Control (CDC) to suggest the re-formulation of the drug to provide antimicrobial activity; i.e., to prevent an increase of microorganism growth of no more than 10 fold in the time period at least 24 hours after adventitious, extrinsic contamination. This action was intended to reduce safety concerns associated with the injection of microbes into patients using the propofol emulsion solution.
In 1996, due to problems related to microbial growth in the soybean oil and egg lecithin, the original formulation was replaced by a new formulation that included the antimicrobial agent EDTA, as detailed by Jones, et al in U.S. Pat. No. 5,714,520. EDTA is a tetrabasic acid and a strong chelator of trace metals such as zinc. As a result, patients using DIPRIVAN® need to be monitored to ensure that zinc levels do not reach a point where zinc deficiency-related adverse affects occur. Also, in rare cases, the EDTA has been reported to have a toxic effect on renal tubes and patients should be periodically monitored in case signs of renal problems occur.
In 1999 another formulation of propofol entered the market. This formulation as detailed in U.S. Pat. No. 6,147,122 by Mirejovsky, et al includes sodium metabisulfite as a preservative. After an extensive testing process it was determined that sulfites can be included in oil-in-water emulsions in non-toxic amounts within the soluble phase without partitioning the organic phase or adversely effecting the formulation. While sodium metabisulfite does not inherently cause toxic side effects, it may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people with sulfite sensitivity.
Ideally a formulation of propofol with increases safety would exist that provided microbial growth retardation activity without the side effects that are associated with the currently used additives (EDTA and sodium metabisulfate). Since propofol is a phenol, under optimal conditions it naturally provides microbial growth retardation activity.
The formulation described in U.S. Pat. No. 6,100,302 is an emulsion of Propofol that contains 1-3% of soybean oil to prevent against accidental microbial contamination during long-term IV infusions due to an increased availability of Propofol. However, the formulation containing 2% of soybean oil can not prevent a less than one log increase for E. coli at 48 hours.
Particularly, the formulation comprising 3% of soybean oil has more than a 10-fold increase for E. coli at 24 hours, which fails to meet current industry standards to prevent no more than one log increase in microbial growth at 24 hours. It appears that upon administration this formulation may also increase the problem of pain on injection due to a higher partition of Propofol in the aqueous phase. This has been studied by M. Eriksson, et al 1997.
In U.S. Pat. No. 6,399,087 Zhang, et al disclosed a propofol emulsion formulation with lower amounts of both soybean oil and egg lecithin and a lower pH. The formulation provides a base to enhance the phenol function of propofol itself, thus allowing the propofol to act as the microbial growth retardant agent. However, in order to get optimal microbial growth retardation, this type of additive-free formulation can reach suitable levels of propofol within the emulsion particles, the aqueous phase, and the liposome particles. The background included herein details the relative ease under which the emulsion particles and aqueous phase rapidly reach equilibrium with sufficient levels of propofol therein. However, it also details the slower equilibrium between the liposome particles and the aqueous phase, and processes for improving the dynamics of the equilibrium which improves the situation where the liposome particles is unacceptable as a nutritional source, in order to prevent the growth of microorganisms.
A search of the prior art did not disclose any patents that read directly on the claims of the instant invention, however the following U.S. patents are considered related:
INVENTORISSUEDU.S. PAT. NO.5,637,625HaynesJune 19975,714,520Jones, et alFebruary 19986,028,108GeorgeFebruary 20006,100,302Pejaver, et alAugust 20006,147,122Mirejovsky, et alNovember 20006,399,087Zhang, et alJanuary 2002OTHER PATENTSWO99/396,96Mirejovsky, et alAugust 1999WO00/243,76May, et alMay 2000